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Molecular and clinical analyses of two patients with UPD(16)mat detected by screening 94 patients with Silver-Russell syndrome phenotype of unknown aetiology
  1. Takanobu Inoue1,2,
  2. Hideaki Yagasaki3,
  3. Junko Nishioka4,
  4. Akie Nakamura1,5,
  5. Keiko Matsubara1,
  6. Satoshi Narumi1,
  7. Kazuhiko Nakabayashi6,
  8. Kazuki Yamazawa1,
  9. Tomoko Fuke1,
  10. Akira Oka2,
  11. Tsutomu Ogata1,7,
  12. Maki Fukami1,
  13. Masayo Kagami1
  1. 1 Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan
  2. 2 Department of Pediatrics, University of Tokyo, Tokyo, Japan
  3. 3 Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Japan
  4. 4 Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
  5. 5 Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan
  6. 6 Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan
  7. 7 Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan
  1. Correspondence to Dr Masayo Kagami, Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan; kagami-ms{at}


Background Recently, a patient with maternal uniparental disomy of chromosome 16 (UPD(16)mat) presenting with Silver-Russell syndrome (SRS) phenotype was reported. SRS is characterised by growth failure and dysmorphic features.

Objective To clarify the prevalence of UPD(16)mat in aetiology-unknown patients with SRS phenotype and phenotypic differences between UPD(16)mat and SRS.

Methods We studied 94 patients with SRS phenotype of unknown aetiology. Sixty-three satisfied the Netchine-Harbison clinical scoring system (NH-CSS) criteria, and 25 out of 63 patients showed both protruding forehead and relative macrocephaly (clinical SRS). The remaining 31 patients met only three NH-CSS criteria, but were clinically suspected as having SRS. To detect UPD(16)mat, we performed methylation analysis for the ZNF597:TSS-differentially methylated region (DMR) on chromosome 16 and subsequently performed microsatellite, SNP array and exome analyses in the patients with hypomethylated ZNF597:TSS-DMR.

Results We identified two patients (2.1%) with a mixture of maternal isodisomy and heterodisomy of chromosome 16 in 94 aetiology-unknown patients with SRS phenotype. Both patients exhibited preterm birth and prenatal and postnatal growth failure. The male patient had ventricular septal defect and hypospadias. Whole-exome sequencing detected no gene mutations related to their phenotypes.

Conclusion We suggest considering genetic testing for UPD(16)mat in SRS phenotypic patients without known aetiology.

  • maternal uniparental disomy of chromosome 16
  • silver-russell syndrome
  • netchine-harbison clinical scoring system
  • znf597

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  • Contributors Molecular analysis was performed by TI, AN, KM, SN and KN. Detailed clinical data and materials for molecular studies were provided by HY, JN, KY, TF and TO. The study was designed and coordinated by MK. The paper was written by TI and MK and reviewed and edited by AO and MF.

  • Funding This work was supported by Grants from the Japan Society for the Promotion of Science (JSPS) (15K15096), the National Center for Child Health and Development (28-6), the Japan Agency for Medical Research and Development (AMED) (16ek0109030h0003, 17ek0109141h0003, 17ek0109278h0001), Takeda Science Foundation and The Japanese Society for Pediatric Endocrinology Future Development Grant.

  • Competing interests None declared.

  • Patient consent Parental/guardian consent obtained.

  • Ethics approval This study was approved by the Institutional Review Board Committee at the National Center for Child Health and Development (committee’s reference number: 518).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice This article has been corrected since it was published Online First. The following supplementary files have been updated: supplementary figure 1, supplementary tables 2 and 3, and supplementary methods.

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